Spinal cord injury (SCI) is among the most disabling conditions affecting wounded members of the U.S. military. Unfortunately, no effective treatment has been available for SCI patients. Developing novel repair strategies to mitigate the devastating nature of SCI and translating them clinically are urgent medical needs that will improve quality of life of our veterans with SCI. The lumbar motoneurons (MNs) are the final common pathway for motor output to the hindlimbs. Any impairment of these MNs can cause hindlimb paralysis and muscle atrophy. The lumbar MNs could be impaired by a direct injury to the lumbar cord or by an indirect injury occurring at levels above the lumbar cord at cervical or thoracic levels (called above-level injuries). For the latter, the lumbar MNs are not directly injured by the trauma, but they undergo profound dendritic atrophy and synaptic stripping from denervated supraspinal and propriospinal axons. Such altered MN morphological and synaptic changes could result in impaired motor outputs to hindlimb muscles and therefore impaired locomotor functions. While most SCI studies have been focused on the regeneration or protection of injured spinal cord at the site of injury, few studies have explored how modulation of lumbar MN circuitry would affect pathological and functional consequences after an above-level SCI. The goal of our research is to understand how lumbar MNs are altered anatomically and functionally after an above-level SCI and how a beneficial restorative treatment affects their reorganization and functional consequences. Neurotrophins are a family of proteins that regulate neuronal survival, neurite outgrowth, synaptic plasticity and neurotransmission. Among them, Neurotrophin-3 (NT-3) plays a particular role in motor restoration by promoting axon growth and synaptic plasticity in multiple spinal pathways. Exogenous administration of NT-3 has been proposed as one potential therapeutic treatment for SCI. This allows us to propose the first hypothesis that the release of retrogradely transported NT-3 from MNs will result in an elevation of local NT-3 levels around the MN pools, promoting remodeling of lumbar motor circuitry, and enhancing physiological and behavioral recoveries following an above-level SCI. We and others also showed exercise training alone improved coordinated motor function following SCIs. Exercise training also contributed to the increased levels of intraspinal neurotrophic factors that promote neuronal survival and plasticity, to the reorganization of neuronal circuitry, and to improvements in synaptic function and behavior. Therefore, we propose the second hypothesis that exercise training will synergistically enhance the effect of NT-3 perhaps by remodeling the spared descending spinal circuits and facilitating the formation of their functional connections with lumbar MNs. Using an adult mouse T9 moderate contusive SCI model and an adeno-associated virus serotype 2 vector encoding NT-3 (AAV2-NT-3) gene transfer approach, we propose 3 Specific Aims to etermine the mechanism by which NT-3 improves recovery after SCI and the long-term efficacy of the NT-3 that (1) d treatment using a clinically feasible delivery route, (2) determine whether exercise training will enhance the effects of NT-3 on the remodeling of lumbar MN circuitry and functional recovery after an above-level SCI, and (3) determine the functional roles of specific descending pathways to lumbar MNs in their ability to modulate lumbar neural circuitry and functional recovery after the optimal treatment. Completion of this proposal will not only allow us to reveal fundamental mechanisms of NT-3/exercise training-mediated remodeling of MN circuitry but also to identify new therapeutic strategies targeting hindlimb locomotor recovery.